The long-term objective of this proposal is to elucidate the mechanisms by which chronic alcohol (EtOH) ingestion predisposes the host to pulmonary infections. In spite of years of extensive research, the precise mechanisms whereby pulmonary infections develop in alcoholics are not fully elucidated. Therefore, novel approaches need to be undertaken to further our understanding of how these infections develop. Based on the gaps in our understanding of why alcoholics have a greater propensity to acquire lung infections, and the recently discovered pivotal role for apoptosis in health and diseases, the project proposes to test three hypotheses: 1) EtOH alters basal rate of lung apoptosis. The primary targets of this EtOH effect are the alveolar macrophages (AM) and during an infection, also infiltrating cells; 2) EtOH alters apoptosis of lung immune cells by modulating the amount and interaction of apoptotic protein adapters; and 3) The EtOH-induced apoptotic death of lung cells overwhelms the inherent clearance mechanisms in the lung. As a result, the uncleared dead cells undergo secondary, necrosis leading to persistent lung inflammation. Accordingly, the proposal has four specific aims: 1) to determine the temporal relationship between EtOH-altered rate of lung apoptosis and severity of infection; 2) to determine the lung cell types undergoing apoptosis following EtOH ingestion and infection; 3) to determine the mechanism(s) underlying EtOH effects on lung immune cell apoptosis and 4) to determine the temporal relationship between EtOH-induced alterations in the kinetics of lung apoptosis and the ability of AM to remove apoptotic cells. To achieve these goals, mice will be fed EtOH for various periods and infected with Streptococcus pneumoniae (SP). These mice will be used to assess the apoptotic and pathologic state of the lung. To evaluate the potential deleterious effects of EtOH enhanced lung cell apoptosis, the lung propensity, to clear an SP infection, will be evaluated in presence and absence of apoptosis inhibitors. By applying biochemical, molecular and cell biology techniques, the steps of apoptotic signaling pathway where EtOH acts will be established. Finally, the project will determine if there is a correlation between EtOH-induced apoptosis, decreased phagocytosis, and increased inflammation. The project will provide essential and novel information to: 1) broaden our understanding of how EtOH increases the hosts' susceptibility to pulmonary infections and 2) pave the way to developing therapeutic interventions to control pulmonary infections.